Normal movement of stool through the colon depends on periodic contractions of the muscles in the wall of the colon that push (or squeeze) fecal matter in the direction of the rectum, which ultimately results in evacuation of the feces. These contractions normally are stimulated by nerves arising from the lower or sacral part of the spinal cord (i.e., S2-4). The effects of these nerves on the colon are generally mediated by a substance called acetylcholine, which causes muscles in the wall of the colon to contract.
The neural control mechanisms of the gastrointestinal (GI) tract are thought to be (or to become) impaired, at least in part, in a number of diseases and medical conditions, e.g., spinal cord injury, amyotrophic lateral sclerosis, spina bifida, multiple sclerosis, Parkinson's disease and dementias, even though the colonic muscles remain intact and capable of responding to acetylcholine. As a result, persons afflicted with these conditions often experience difficulty with bowel functions, including the inability to initiate defecation, straining to defecate, or incomplete evacuation of feces. Because of the chronic nature of the underlying disease, the resulting bowel dysfunction is also chronic and may have a significant negative impact on the subject's quality of life.
Traditional approaches to bowel care for individuals with chronic bowel dysfunction typically involve the periodic administration of laxatives and enemas in combination with digital stimulation of the rectum. These approaches are time consuming and expensive, have unpredictable efficacy, and may cause damage to the bowel. For example, incomplete emptying of the bowel at the time of bowel care increases the likelihood of incontinence, i.e., “accidents.” Moreover, the physical trauma of bowel care procedures leads to an increased risk of anorectal problems, especially bleeding hemorrhoids and anal fissures.
Neostigmine is a drug that has long been used by anesthesiologists to reverse the muscle paralysis artificially induced during surgical procedures. Neostigmine is a reversible acetylcholinesterase inhibitor, which blocks the breakdown of the neurotransmitter acetylcholine. This results in an accumulation of acetylcholine in synaptic spaces, which causes (among other things) contractions of the smooth muscles of the bowel.
While smooth muscle contractions in the gut were considered an unwanted side effect by anesthesiologists, other clinicians (e.g., Ponec et al., New Engl. J. Med., 341(3):137-141, 1999) have exploited this neostigmine effect in the treatment of acute colonic pseudo-obstruction. Acute colonic pseudo-obstruction is a relatively rapid onset, intense, short-term condition characterized by bowel distension, constipation, abdominal pain, and the absence of an actual mechanical blockage. Following neostigmine administration for this condition, most patients successfully passed flatus or stool with a corresponding reduction in abdominal distention. However, as expressly recognized by Ponec et al., neostigmine treatment is not without risk. Known side effects of neostigmine include bradycardia (i.e., slowing of the heart rate), excessive pharyngeal and laryngeal secretions, nausea, vomiting, abdominal cramps, and diarrhea. In particular, neostigmine-induced bradycardia can become life threatening and requires close cardiac monitoring in a clinical setting.
Glycopyrrolate is an anti-cholinergic agent (more particularly, a muscarinic antagonist), which blocks neurotransmission by acetylcholine. Glycopyrrolate (or other anti-cholinergic agents, such as atropine) are used by anesthesiologists in the operating room setting or by other clinicians in clinical settings and essentially on emergency basis to counteract the cardiac side effects (e.g., bradycardia) caused by neostigmine.
The potentially life-threatening side effects of neostigmine have historically restricted its usefulness to the clinical setting where the drug recipient is carefully monitored. Even though medications, such as glycopyrrolate, are available to counteract the side effects of neostigmine, those medications have traditionally been administered non-repetitively in the clinical setting only at the time the side effects of neostigmine are induced. For all of these reasons, the routine use of neostigmine for the treatment of a chronic medical condition in a non-clinical setting has been considered unacceptable.
Thus, there remains a need for improved compositions and methods for treating chronic intestinal pseudo-obstruction, such as occurs as a result of spinal cord injury and other medical conditions and disorders.